This invention relates to macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to methods of preparing the compounds, intermediates useful in preparation of the compounds, and pharmaceutical compositions containing the compounds. In addition, the present invention includes methods of treating bacterial and protozoal infections through the administration of the compounds to mammals, fish and birds requiring such treatment.
Derivatives of erythromycin A that are useful as antibiotic agents are referred to in International patent applications WO 98/56800, published Dec. 17, 1998; WO 98/51696, published Nov. 19, 1998; WO 99/21866, published May 6, 1999; WO 99/62920, published Dec. 9, 1999; WO 99/21865, published May 6, 1999; PCT/IB99/01701, filed Oct. 18, 1999; European patent application EP 895999, published Feb. 10, 1999; U.S. patent application Ser. No. 60/117,342, filed Jan. 27, 1999; U.S. patent application Ser. No. 60/130,809, filed Apr. 23, 1999; U.S. patent application Ser. No. 60/130,912, filed Apr. 23, 1999; and U.S. patent application Ser. No. 60/130,913, filed Apr. 23, 1999. Derivatives of erythromycin A are also referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, relating to the commercially available antibiotic azithromycin. These patents and patent applications are incorporated by reference herein in their entireties.
The present invention relates to compounds of the formula 
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
X is C, Br, I, or F;
Y is xe2x95x90O, or xe2x95x90NOR5 or Y means both xe2x80x94H and xe2x80x94OR5; or both xe2x80x94H and xe2x80x94NR5R10 (i.e. Y is double bonded to the macrolide ring where it is xe2x95x90O or xe2x95x90NOR5, or refers to two single bonded groups where it is both xe2x80x94H and xe2x80x94OR5; or both xe2x80x94H and xe2x80x94NR5R10);
R1, R2, and R3 are independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, (4- to 10-membered heterocyclic) C1-C6 alkyl, (4- to 10-membered heterocyclic) C2-C6 alkenyl, (4- to 10-membered heterocyclic) C2-C6 alkynyl, (C6-C10 aryl) C1-C6 alkyl, (C6-C10 aryl) C2-C6 alkenyl, and (C6-C10 aryl) C2-C6 alkynyl wherein said alkyl moieties of the foregoing groups are optionally substituted by halo or C1-C6 alkyl, and wherein said heterocyclic moieties are optionally substituted by 4- to 10-membered heterocyclic, (4- to 10-membered heterocyclic) C1-C6 alkyl, or (C6-C10 aryl) C1-C6 alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents is optionally substituted by 1 to 4 R7 groups;
R4 is selected from H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy) C1-C6 alkyl, (C1-C6 alkylthio) C1-C6 alkyl, (C5-C8 cycloalkyl) C2-C5 alpha branched alkyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3 to 6 membered O or S containing heterocyclic group, or phenyl, wherein each R4 group may be substituted with from 1 to 3 substituents independently selected from hydroxy, halo, (C6-C10 aryl) C2-C6 alkenyl, and C1-C4 alkyl;
R5 and R10 are independently selected from H, C1-C6 alkyl, C6-C10 aryl, 4- to 10-membered heterocyclic, (4- to 10-membered heterocyclic) C1-C6 alkyl and (C6-C10 aryl) C1-C6 alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R7 groups;
R6 is H, xe2x80x94C(O)C1-C6 alkyl, benzyl, benzyloxycarbonyl, or (C1-C6 alkyl)3 silyl;
R7 is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94NR8C(O)R9, xe2x80x94C(O)NR8R9, xe2x80x94NR8R9, hydroxy, C1-C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 4- to 10-membered heterocyclic, and C1-C6 alkoxy; and
each R8 and R9 is independently selected from H, C1-C6 alkyl, C6-C10 aryl, and 4- to 10-membered heterocyclic.
In one embodiment of the invention, Y is xe2x95x90O or xe2x95x90NOR5, R1 is (4- to 10-membered heterocyclic) C1-C6 alkyl substituted by 4- to 10-membered heterocyclic, R2 is C1-C10 alkyl or C2-C10 alkenyl, R3 is C1-C6 alkyl, R4 is ethyl, R5 is C1-C6 alkyl, and R6 is H.
In another embodiment, the compound of the invention has the following formula: 
In one embodiment of the compound of formula la, Y is xe2x95x90O or xe2x95x90NOR5, R2 is C1-C10 alkyl or C2-C10 alkenyl, and R6 is H, xe2x80x94C(O)C1-C6 alkyl, benzyl, benzyloxycarbonyl, or (C1-C6 alkyl)3 silyl. In one aspect of this embodiment, Y is xe2x95x90O and R6 is H. In another aspect of this embodiment, Y is xe2x95x90NOR5 and R6 is H. Preferably, in this embodiment, R2 is CH3, CH2CH3, CH2CHxe2x95x90CH2, trans-CH2CHxe2x95x90CHCH3, trans-CH2CHxe2x95x90CHCH2CH3, or trans-CH2xe2x80x94CHxe2x95x90C(CH3)CH2CH2CHxe2x95x90(CH3)CH3.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
As used herein, unless otherwise indicated, the terms xe2x80x9cbacterial infection(s)xe2x80x9d and xe2x80x9cprotozoa infection(s)xe2x80x9d include bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections, and disorders related to such infections, include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionelia pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chiamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), vindans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobactedium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordeteila pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylon or Chlamydia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., xe2x80x9cThe Sanford Guide To Antimicrobial Therapy,xe2x80x9d 26th Edition, (Antimicrobial Therapy, Inc., 1996).
The present invention also relates to a method of preparing the above compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises deprotecting a compound of the formula 
wherein P is a protecting group.
In a further aspect of the above process of preparing the compound of formula I, or a pharmaceutically acceptable salt thereof, the above compound of formula II is prepared by treating a compound of the formula 
with a strong base and a compound of formula R2-L, where L is a leaving group.
The term xe2x80x9cMexe2x80x9d, as used herein, unless otherwise indicated, refers to methyl.
The term xe2x80x9cEtxe2x80x9d, as used herein, unless otherwise indicated, refers to ethyl.
The term xe2x80x9cPrxe2x80x9d, as used herein, unless otherwise indicated, refers to propyl.
The term xe2x80x9cAcxe2x80x9d, as used herein, unless otherwise indicated, refers to acetyl.
The term xe2x80x9chydroxy protecting groupxe2x80x9d, as used herein, unless otherwise indicated, includes acetyl, benzyloxycarbonyl, and various hydroxy protecting groups familiar to those skilled in the art including the groups referred to in T. W. Greene, P. G. M. Wuts, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (J. Wiley and Sons, 1991). 
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties, or mixtures thereof. It is to be understood that where cyclic moieties are intended, at least three carbons in said alkyl must be present. Such cyclic moieties include cyclopropyl, cyclobutyl and cyclopentyl.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radicals containing at least one carbon-carbon double bond. Examples of alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z,Z-hexadienyl and the like.
The term xe2x80x9calkynylxe2x80x9d, as used herein, unless otherwise indicated, includes straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes xe2x80x94 alkyl groups wherein alkyl is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term xe2x80x9c4- to 10-membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxygen or nitrogen atoms. The heterocyclic groups also include partially unsaturated or fully saturated 4- to 10-membered ring systems, e.g., single rings of 4 to 8 atoms in size and bi- or tricyclic ring systems, including aromatic 6-membered aryl or heteroaryl rings fused to a non-aromatic ring. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
The term xe2x80x9cprotecting groupxe2x80x9d refers to a suitable chemical group that may be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T. W. Greene and P. G. M Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser""s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric and diastereomic forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
The present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
The compounds of this invention, including the compounds of formula I, include pharmaceutically acceptable derivatives or prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivative or prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or a metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), enhance delivery of the parent compound to a given biological compartment, increase solubility to allow administration by injection, alter metabolism or alter rate of excretion.
Compounds of formula I can be converted into prodrugs through, for example, free amino, amido, hydroxy or carboxylic groups. Examples of such prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of formula I. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. The amide and ester moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher et al., Advanced Drug Delivery Reviews, vol. 19, p. 115 (1996). Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in R. P. Robinson et al., J. Medicinal Chemistry, vol. 39, p. 10 (1996).
The compounds of this invention also include pharmaceutically acceptable salts of the compounds of formula I. The term xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention.
Compounds of the invention may exist in tautomeric form. All tautomers of the compounds of formula I are included in the invention.